tbuckley/cabot-search huggingface dataset:
Clinical and Pathological Features and Gene Expression Profiles of Clinically Aggressive Papillary Thyroid Carcinomas
Authors: Jasna Metovic, Francesco Cabutti, Simona Osella-Abate, Giulia Orlando, Cristian Tampieri, Francesca Napoli, Francesca Maletta, Lorenzo Daniele, Marco Volante, Mauro Papotti
Journal: Endocrine Pathology (2023)

Abstract Papillary thyroid carcinoma (PTC) is considered an indolent neoplasm but it may demonstrate aggressive behavior. We aimed to identify clinical and pathological characteristics and molecular signatures associated with aggressive forms of PTCs. We selected 43 aggressive PTC cases based on the presence of metastases at the time of diagnosis, the development of distant metastasis during follow-up, and/or biochemical recurrence, and 43 PTC patients that were disease-free upon follow-up, matching them according to age, sex, pT, and pN parameters. Twenty-four pairs (a total of 48 cases) and 6 normal thyroid tissues were studied using targeted mRNA screening of cancer-associated genes employing NanoString nCounter ® technology. In general, aggressive PTCs showed distinctive clinical and morphological features. Among adverse prognostic parameters, the presence of necrosis and an increased mitotic index were associated with shorter disease-free and overall survivals. Other parameters associated with shorter disease-free or overall survivals include a lack of tumor capsule, the presence of vascular invasion, tumor-infiltrating lymphocytes, fibrosclerotic changes, age &gt; 55 years, and a high pTN stage. Various pathways were differentially regulated in non-aggressive as compared to aggressive PTC, including the DNA damage repair, the MAPK, and the RAS pathways. In particular, the hedgehog pathway was differentially de-regulated in aggressive PTC as compared to non-aggressive PTC cases, being WNT10A and GLI3 genes significantly up- and down-regulated in aggressive PTC and GSK3B up-regulated in non-aggressive PTC cases. In conclusion, our study revealed specific molecular signatures and morphological features in aggressive PTC that may be useful to predict more aggressive behavior in a subset of PTC patients. These findings may be useful when developing novel, tailored treatment options for these patients.
Targeting CD44 Variant 5 with an Antibody–Drug Conjugate Is an Effective Therapeutic Strategy for Intrahepatic Cholangiocarcinoma
Authors: Yuncheng Bei, Jian He, Xuhui Dong, Yuxin Wang, Sijie Wang, Wan Guo, Chengjie Cai, Zhiye Xu, Jia Wei, Baorui Liu, Nan Zhang, Pingping Shen
Journal: Cancer Research (2023)

Intrahepatic cholangiocarcinoma (ICC) is the second most frequent type of primary liver cancer. ICC is among the deadliest malignancies, highlighting that novel treatments are urgently needed. Studies have shown that CD44 variant isoforms, rather than the CD44 standard isoform, are selectively expressed in ICC cells, providing an opportunity for the development of an antibody-drug conjugate (ADC)-based targeted therapeutic strategy. In this study, we observed the specific expression of CD44 variant 5 (CD44v5) in ICC tumors. CD44v5 protein was expressed on the surface of most ICC tumors (103 of 155). A CD44v5-targeted ADC, H1D8-DC (H1D8-drug conjugate), was developed that comprises a humanized anti-CD44v5 mAb conjugated to the microtubule inhibitor monomethyl auristatin E (MMAE) via a cleavable valine-citrulline-based linker. H1D8-DC exhibited efficient antigen binding and internalization in cells expressing CD44v5 on the cell surface. Because of the high expression of cathepsin B in ICC cells, the drug was preferentially released in cancer cells but not in normal cells, thus inducing potent cytotoxicity at picomolar concentrations. In vivo studies showed that H1D8-DC was effective against CD44v5-positive ICC cells and induced tumor regression in patient-derived xenograft models, whereas no significant adverse toxicities were observed. These data demonstrate that CD44v5 is a bona fide target in ICC and provide a rationale for the clinical investigation of a CD44v5-targeted ADC-based approach.Elevated expression of CD44 variant 5 in intrahepatic cholangiocarcinoma confers a targetable vulnerability using the newly developed antibody-drug conjugate H1D8-DC, which induces potent growth suppressive effects without significant toxicity.
Stress, diet, exercise: Common environmental factors and their impact on epigenetic age
Authors: Fedor Galkin, Olga Kovalchuk, Diana Koldasbayeva, Alex Zhavoronkov, Evelyne Bischof
Journal: Ageing Research Reviews (2023)

Epigenetic aging clocks have gained significant attention as a tool for predicting age-related health conditions in clinical and research settings. They have enabled geroscientists to study the underlying mechanisms of aging and assess the effectiveness of anti-aging therapies, including diet, exercise and environmental exposures. This review explores the effects of modifiable lifestyle factors' on the global DNA methylation landscape, as seen by aging clocks. We also discuss the underlying mechanisms through which these factors contribute to biological aging and provide comments on what these findings mean for people willing to build an evidence-based pro-longevity lifestyle.
Issue 2 - “Update on adverse respiratory effects of indoor air pollution”. Part 2): Indoor air pollution and respiratory diseases: Perspectives from Italy and some other GARD countries
Authors: G. Sarno, I. Stanisci, S. Maio, S. Williams, E.M. Khoo, S.G. Diaz, E.V. Ponte, L.T.T. Lan, T. Soronbaev, D. Behera, S. Tagliaferro, S. Baldacci, G. Viegi
Journal: Pulmonology (2023)

to synthesize the Italian epidemiological contribution to knowledge on indoor pollution respiratory impact, and to analyze the perspective of some GARD countries on the health effects of indoor air pollution. Italian epidemiological analytical studies confirmed a strong relationship between indoor air pollution and health in general population. Environmental tobacco smoke, biomass (wood/coal) fuel for cooking/heating and indoor allergens (house dust mites, cat and dog dander, mold/damp) are the most relevant indoor pollution sources and are related to respiratory and allergic symptoms/diseases in Italy and in other GARD countries such as Mexico, Brazil, Vietnam, India, Nepal and Kyrgyzstan. Community-based global health collaborations are working to improve prevention, diagnosis and care of respiratory diseases around the world, specially in low- and middle-income countries, through research and education. in the last thirty years, the scientific evidence produced on respiratory health effects of indoor air pollution has been extensive, but the necessity to empower the synergies between scientific community and local administrations remains a challenge to address in order to implement effective interventions. Based on abundant evidence of indoor pollution health effect, WHO, scientific societies, patient organizations and other members of the health community should work together to pursue the GARD vision of "a world where all people breathe freely" and encourage policy makers to increase their engagement in advocacy for clean air.
Definition and Diagnosis of Oligometastatic Bladder Cancer: A Delphi Consensus Study Endorsed by the European Association of Urology, European Society for Radiotherapy and Oncology, and European Society of Medical Oncology Genitourinary Faculty
Authors: Aristotelis Bamias, Arnulf Stenzl, Stephanie L. Brown, Laurence Albiges, Marko Babjuk, Alison Birtle, Alberto Briganti, Maximilian Burger, Ananya Choudhury, Maurizio Colecchia, Maria De Santis, Stefano Fanti, Valérie Fonteyne, Michele Gallucci, Juan Gómez Rivas, Robert Huddart, Kerstin Junker, Stephanie Kroeze, Yohann Loriot, Axel Merseburger, Rodolfo Montironi, Andrea Necchi, Christoph Oing, Jan Oldenburg, Piet Ost, Michael Pinkawa, Maria J. Ribal, Morgan Rouprêt, Harriet Thoeny, Thomas Zilli, Peter Hoskin
Journal: European Urology (2023)
Accounting for the strangeness, infrequency, and suddenness of déjà vu
Authors: Nikola Andonovski, Kourken Michaelian
Journal: Behavioral and Brain Sciences (2023)

Barzykowski and Moulin argue that déjà vu is a natural product of autobiographical memory retrieval. Their proposal fails to account for three salient properties of déjà vu experiences: Their strangeness, their infrequency, and their characteristically sudden onset. Accounting for these properties is necessary for proper integration of déjà vu into autobiographical memory research.
Differences and similarities in teledermatological primary care case histories between people with different skin tones
Authors: Iris R Vroom, Maaike A Hulshof, Willeke Schelhaas, Steven N Koning, Sanne M Sanavro, Henk van der Worp, Daniëlle E M C Jansen, Marco H Blanker
Journal: British Journal of Dermatology (2023)

Evaluation of teleconsultations on the Prisma platform revealed differences in the type of questions posted by Dutch general practitioners and advice received from dermatologists regarding people with skin of colour (SOC) and those with white skin. A survey of users of this interdisciplinary platform confirmed low competence in recognizing and treating problems in people with SOC, and a need for additional education to provide care for people with SOC identified.
Defective cathepsin Z affects <i>EGFR</i> expression and causes autosomal dominant palmoplantar keratoderma
Authors: Kiril Malovitski, Ofer Sarig, Yarden Feller, Shir Bergson, Sari Assaf, Janan Mohamad, Mor Pavlovsky, Moshe Giladi, Eli Sprecher
Journal: British Journal of Dermatology (2023)

The abnormal function of epidermal growth factor receptor (EGFR) has recently been shown to underlie various disorders of cornification.To delineate the genetic basis of a novel dominant form of palmoplantar keratoderma (PPK).Whole-exome (WES) and direct sequencing, quantitative real-time polymerase chain reaction, protein modelling, confocal immunofluorescence microscopy, immunoblotting, three-dimensional skin equivalents and an enzyme activity assay were used to delineate the genetic basis of a novel dominant form of PPK.WES revealed heterozygous variants (c.274T > C and c.305C > T) in CTSZ (encoding cathepsin Z) in four individuals (belonging to three unrelated families) with focal PPK. Bioinformatics and protein modelling predicted the variants to be pathogenic. Previous studies have suggested that EGFR expression may be subject to cathepsin regulation. Immunofluorescence revealed reduced cathepsin Z expression in the upper epidermal layers and concomitant increased epidermal EGFR expression in patients harbouring CTSZ variants. Accordingly, human keratinocytes transfected with constructs expressing PPK-causing variants in CTSZ displayed reduced cathepsin Z enzymatic activity, as well as increased EGFR expression. In line with the role played by EGFR in the regulation of keratinocyte proliferation, human keratinocytes transfected with the PPK-causing variants showed significantly increased proliferation that was abolished upon exposure to erlotinib, an EGFR inhibitor. Similarly, downregulation of CTSZ resulted in increased EGFR expression and increased proliferation in human keratinocytes, suggestive of a loss-of-function effect of the pathogenic variants. Finally, three-dimensional organotypic skin equivalents grown from CTSZ-downregulated cells showed increased epidermal thickness and EGFR expression as seen in patient skin; here, too, erlotinib was found to rescue the abnormal phenotype.Taken collectively, these observations attribute to cathepsin Z a hitherto unrecognized function in epidermal differentiation.
Prevalence of psoriasis and other autoimmune skin diseases in a recently contacted indigenous community in the Auaris region, Yanomami Indigenous Territory, Brazil
Authors: Ricardo Romiti, Luciana P F Martins, Yago R T Santana, Renata V Timbó, Patrícia S Kurizky, Daniel H Barroso, Rafael R de Andrade, Ciro M Gomes, Christopher E M Griffiths
Journal: British Journal of Dermatology (2023)

Previous studies have discussed the low prevalence of psoriasis among indigenous peoples of South America. The state of Roraima, Brazil, where the present study was performed, is crossed by the equator line. It is likely that key factors for the absence of psoriasis in this indigenous population include genetic factors, a lack of environmental triggers and high sun exposure.
Patient-reported influences on COVID-19 vaccine acceptance and hesitancy in people with hidradenitis suppurativa
Authors: Jazzmin C Williams, Raed Alhusayen, Sandra Guilbault, John R Ingram, Michelle A Lowes, Christine A Yannuzzi, Haley B Naik
Journal: British Journal of Dermatology (2023)

COVID-19 continues to pose a risk to patients with hidradenitis suppurativa (HS) due to the high prevalence of comorbidities associated with severe COVID-19 disease. We aimed to characterize perspectives on COVID-19 vaccination among patients with HS. International respondents from 20 online HS support groups were recruited to complete a voluntary, anonymous, online cross-sectional survey from 25 October to 21 November 2021 to obtain perspectives from people with HS who may and may not access healthcare. We report higher rates of COVID-19 vaccine hesitancy among patients with HS who expressed dissatisfaction with their dermatological care.
Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction According to Polypharmacy Status
Authors: Alexander Peikert, Parag Goyal, Muthiah Vaduganathan, Brian L. Claggett, Ian J. Kulac, Zi Michael Miao, Orly Vardeny, Mikhail N. Kosiborod, Akshay S. Desai, Pardeep S. Jhund, Carolyn S.P. Lam, Silvio E. Inzucchi, Felipe A. Martinez, Rudolf A. de Boer, Adrian F. Hernandez, Sanjiv J. Shah, Magnus Petersson, Anna Maria Langkilde, John J.V. McMurray, Scott D. Solomon
Journal: JACC Heart Failure (2023)
Longitudinal Asthma Phenotypes from Childhood to Middle-Age: A Population-based Cohort Study
Authors: Daniel J. Tan, Caroline J. Lodge, E. Haydn Walters, Adrian J. Lowe, Dinh S. Bui, Gayan Bowatte, Jonathan Pham, Bircan Erbas, Jennie Hui, Garun S. Hamilton, Paul S. Thomas, Mark Hew, George Washko, Richard Wood-Baker, Michael J. Abramson, Jennifer L. Perret, Shyamali C. Dharmage
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Asthma is a heterogeneous condition, and longitudinal phenotyping may provide new insights into the origins and outcomes of the disease. Objectives: We aimed to characterize the longitudinal phenotypes of asthma between the first and sixth decades of life in a population-based cohort study. Methods: Respiratory questionnaires were collected at seven time points in the TAHS (Tasmanian Longitudinal Health Study) when participants were aged 7, 13, 18, 32, 43, 50, and 53 years. Current-asthma and ever-asthma status was determined at each time point, and group-based trajectory modeling was used to characterize distinct longitudinal phenotypes. Linear and logistic regression models were fitted to investigate associations of the longitudinal phenotypes with childhood factors and adult outcomes. Measurements and Main Results: Of 8,583 original participants, 1,506 had reported ever asthma. Five longitudinal asthma phenotypes were identified: early-onset adolescent-remitting (40%), early-onset adult-remitting (11%), early-onset persistent (9%), late-onset remitting (13%), and late-onset persistent (27%). All phenotypes were associated with chronic obstructive pulmonary disease at age 53 years, except for late-onset remitting asthma (odds ratios: early-onset adolescent-remitting, 2.00 [95% confidence interval (CI), 1.13-3.56]; early-onset adult-remitting, 3.61 [95% CI, 1.30-10.02]; early-onset persistent, 8.73 [95% CI, 4.10-18.55]; and late-onset persistent, 6.69 [95% CI, 3.81-11.73]). Late-onset persistent asthma was associated with the greatest comorbidity at age 53 years, with increased risk of mental health disorders and cardiovascular risk factors. Conclusions: Five longitudinal asthma phenotypes were identified between the first and sixth decades of life, including two novel remitting phenotypes. We found differential effects of these phenotypes on risk of chronic obstructive pulmonary disease and nonrespiratory comorbidities in middle age.
Impact of Early Hemodynamic Screening on Extremely Preterm Outcomes in a High-Performance Center
Authors: Regan E. Giesinger, Danielle R. Rios, Trassanee Chatmethakul, Adrianne R. Bischoff, Jeremy A. Sandgren, Alison Cunningham, Madeline Beauchene, Amy H. Stanford, Jonathan M. Klein, Patrick Ten Eyck, Patrick J. McNamara
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Increasing survival of extremely preterm infants with a stable rate of severe intraventricular hemorrhage represents a growing health risk for neonates.
Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid
Authors: Pablo Garcia-Pavia, Fabian aus dem Siepen, Erwan Donal, Olivier Lairez, Peter van der Meer, Arnt V. Kristen, Michele F. Mercuri, Aubin Michalon, Robert J.A. Frost, Jan Grimm, Roger M. Nitsch, Christoph Hock, Peter C. Kahr, Thibaud Damy
Journal: New England Journal of Medicine (2023)

Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there is no available treatment that depletes ATTR from the heart for the amelioration of cardiac dysfunction. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells. Download a PDF of the Research Summary. In this phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. Patients were sequentially enrolled in six cohorts that received ascending doses (ranging from 0.3 to 60 mg per kilogram of body weight). After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed. The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro–B-type natriuretic peptide and troponin T levels also seemed to be reduced. In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.) QUICK TAKE VIDEO SUMMARYAntibody NI006 for Depletion of Cardiac Transthyretin Amyloid 02:32
Harnessing big data for health equity through a comprehensive public database and data collection framework
Authors: Cameron Sabet, Alessandro Hammond, Nim Ravid, Michelle Sun Tong, Fatima Cody Stanford
Journal: npj Digital Medicine (2023)

Abstract The United States Department of Health and Human Services (HHS) pledged $90 million to help reduce health disparities with data-driven solutions. The funds are being distributed to 1400 community health centers, serving over 30 million Americans. Given these developments, our piece examines the reasons behind the delayed adoption of big data for healthcare equity, recent efforts embracing big data tools, and methods to maximize potential without overburdening physicians. We additionally propose a public database for anonymized patient data, introducing diverse metrics and equitable data collection strategies, providing valuable insights for policymakers and health systems to better serve communities.
The phospholipid transporter PITPNC1 links KRAS to MYC to prevent autophagy in lung and pancreatic cancer
Authors: Rodrigo Entrialgo-Cadierno, Cristina Cueto-Ureña, Connor Welch, Iker Feliu, Irati Macaya, Laura Vera, Xabier Morales, Sandra Vietti Michelina, Pietro Scaparone, Ines Lopez, Elodie Darbo, Oihane Erice, Adrian Vallejo, Haritz Moreno, Ainhoa Goñi-Salaverri, David Lara-Astiaso, Nils Halberg, Ivan Cortes-Dominguez, Elizabeth Guruceaga, Chiara Ambrogio, Fernando Lecanda, Silve Vicent
Journal: Molecular Cancer (2023)

Abstract Background The discovery of functionally relevant KRAS effectors in lung and pancreatic ductal adenocarcinoma (LUAD and PDAC) may yield novel molecular targets or mechanisms amenable to inhibition strategies. Phospholipids availability has been appreciated as a mechanism to modulate KRAS oncogenic potential. Thus, phospholipid transporters may play a functional role in KRAS-driven oncogenesis. Here, we identified and systematically studied the phospholipid transporter PITPNC1 and its controlled network in LUAD and PDAC. Methods Genetic modulation of KRAS expression as well as pharmacological inhibition of canonical effectors was completed. PITPNC1 genetic depletion was performed in in vitro and in vivo LUAD and PDAC models. PITPNC1 -deficient cells were RNA sequenced, and Gene Ontology and enrichment analyses were applied to the output data. Protein-based biochemical and subcellular localization assays were run to investigate PITPNC1-regulated pathways. A drug repurposing approach was used to predict surrogate PITPNC1 inhibitors that were tested in combination with KRASG12C inhibitors in 2D, 3D, and in vivo models. Results PITPNC1 was increased in human LUAD and PDAC, and associated with poor patients’ survival. PITPNC1 was regulated by KRAS through MEK1/2 and JNK1/2. Functional experiments showed PITPNC1 requirement for cell proliferation, cell cycle progression and tumour growth. Furthermore, PITPNC1 overexpression enhanced lung colonization and liver metastasis. PITPNC1 regulated a transcriptional signature which highly overlapped with that of KRAS, and controlled mTOR localization via enhanced MYC protein stability to prevent autophagy. JAK2 inhibitors were predicted as putative PITPNC1 inhibitors with antiproliferative effect and their combination with KRASG12C inhibitors elicited a substantial anti-tumour effect in LUAD and PDAC. Conclusions Our data highlight the functional and clinical relevance of PITPNC1 in LUAD and PDAC. Moreover, PITPNC1 constitutes a new mechanism linking KRAS to MYC, and controls a druggable transcriptional network for combinatorial treatments. Graphical Abstract